Methods: A systematic review of literature pertaining to BON, oral and intravenous bisphosphonates, CTX and bone biology was undertaken. In addition, recent publications on the resolution of BON with short-term, intermittent administration of teriparatide, the only FDA approved drug with anabolic effect on bone formation, were evaluated.
Results: CTX levels correlate primarily in a subset of patients on oral bisphosphonates whose BON resolved following a drug holiday. A reduced CTX level is not specific to patients who develop BON. In addition, CTX levels correlate poorly in patients on intravenous bisphosphonates who develop BON. Thus, a reduced CTX level is neither necessary nor sufficient for the development of BON.
Conclusions: We propose that impaired bone formation/ bone healing in the face of suppressed bone resorption, rather than arrested bone resorption alone, results in the development of BON. This could explain why the CTX assay reliably predicts BON only in a subset of patients. Successful resolution of BON with teriparatide is additional proof of concept. Our model is consistent with the importance of osteoclast-mediated stimulation of osteoblasts in physiological bone remodeling. We believe that BON may be reliably predicted by measuring the relative balance between bone formation (markers such as bALP, PINP) and resorption (CTX), rather than by measuring resorption alone. Clinical trials to test this hypothesis and determine the efficacy of teriparatide in the management of BON are warranted.